Project Summary/Abstract The brain can be exposed to ionizing irradiation during cancer treatment, and the radiation dose that can be administered safely is dictated by the tolerance of normal tissues surrounding the tumor. Cranial irradiation can induce cognitive impairments that involve the hippocampus, a structure critical for learning and memory. The pathogenesis of cognitive impairment is poorly understood, but there are suggestions of a mechanistic link between such injury and altered hippocampal neurogenesis and/or disruption of neuronal function. Recent studies show that environmental influences such as oxidative stress are involved, suggesting that reactive oxygen species (ROS) may be critical environmental cues for the control of precursor cell survival and differentiation. Thus, oxidative stress and the maintenance of redox homeostasis may play an important role in altered neurogenesis and cognitive impairment after irradiation. The superoxide dismutase (SOD) isoforms mitigate the physiological and pathological effects of ROS. While the specific roles of the SODs are not completely understood, the extracellular isoform (EC-SOD, SOD3) has been shown to be associated with cognitive functions associated with the hippocampus. Alterations in EC- SOD expression impair learning, and hippocampal neurogenesis is reduced in animals deficient in EC-SOD (i.e., EC-SOD knockout (KO) mice). Additionally, when EC-SOD KO mice are exposed to a modest dose of x- rays, an expected decrease in neurogenesis does not occur. Thus, we hypothesize that an alteration in redox homeostasis can have beneficial effects in the context of radiation response in neurogenic populations. To understand how this protective effect works, and if it can ultimately be used to influence potential adverse effects of irradiation in patients, we will need to address issues related to redox homeostasis in the intact animal. Those issues deemed particularly important in this context include the determination of: a) whether EC-SOD deficiency can be turned on or off to affect the protective effects (Aim 1); b) if the protective effect changes with different degrees of oxidative insult (i.e. radiation dose) (Aim 2); c) if there are functional consequences (behavior) of EC-SOD deficiency after irradiation (Aim 3); d) if the protective effect is mediated by the presence of increased numbers endogenous inflammatory cells (microglia) (Aim 4); and e) if the protective effect is due to site specific (neuronal, endothelial) or systemic deficiency of EC-SOD (Aim 5). To address our hypothesis we have developed unique animal models in which we can selectively regulate the temporal expression of EC-SOD. The quantitative assessment of radiation effects will include quantification of neurogenesis, behavioral performance and a molecular determinant associated with learning and memory (the immediate early gene Arc). The ability to quantify and inter-relate these endpoints will provide novel insight about radiation brain injury, and may ultimately contribute to the development of strategies or approaches for the management of a very serious complication of cranial irradiation.